Background therapies can be a significant confounder, muddying the results of an RA clinical trial.
A post-hoc analysis has found that continuing MTX background therapy during two clinical trials had an impact on response in the placebo groups.
The pooled placebo group included patients both with and without ongoing MTX therapy.
The study, led by Professor Andreas Kerschbaumer of the Medical University of Vienna and published in the Annals of the Rheumatic Diseases, investigated whether placebo responses might be related to a more effective intake of MTX during the tightly monitored trial periods.
Background therapies can be a significant confounder, muddying the results of an RA clinical trial. As the analysis suggested MTX intake had affected the placebo response, the research team said their finding could have implications for clinical trial design.
“Background therapies … should be effectively aligned before recruitment of patients into a clinical trial, possibly also through introducing ‘run-in’ phases in future clinical trials,” the team said in its research paper. This might lead to fewer patients being needed for a trial.
Their conclusion also “re-emphasises the importance of adequate MTX treatment and improving compliance in patients diagnosed with RA”.
The study examined the responses of 398 placebo patients from the two trials (the GO-AFTER and SIRROUND-T studies). Of these, 285 continued MTX therapy – and, overall, showed a higher response – while 113 received no background DMARDs.
The difference between the MTX-treated and untreated placebo patients at least supported the idea that patients had shown greater adherence to pre-existing drugs in a clinical trial setting.
The researchers suggested this could be because of the more rigorous monitoring involved in trials, with more frequent visits, closer management and specialised care, and no additional costs.
“Real-world data reveal that patients frequently do not fill their prescriptions, resulting in worse clinical outcomes across specialties (‘adherence gap’), while these drugs are provided in clinical trials and, therefore, adherence/persistence may be higher in trials,” the researchers said.
“The results of our analyses may have to be considered in the future when planning and conducting clinical trials in RA, as every power calculation relies on sufficiently estimated PBO response rates in any population.”
The research team cautioned that adherence was not formally assessed as part of the analysis.
However, the study raises the question of why patients might have shown greater adherence, said Monash University Adjunct Clinical Professor Stephen Hall (who is also a member of the Rheumatology Republic editorial board).
“Patients were not controlled for why they were or weren’t on background methotrexate,” Professor Hall said, “and so given that, biases may have come in and then the biases may speak to the belief systems and the relationship between the patient and their doctor, and the fact that they’ve been trained to be more adherent and therefore more likely to have a placebo response.”
There were three aspects to response, he said.
“There’s the psychological dimension, which is the belief that ‘I’m on a treatment’.
“We’ve got a physical dimension – because it’s quite clear from functional MRI there is a linkage between placebo response and activation of the cortex, blurring the lines between mind and body.
“And then we’ve got a third one, which is what this analysis refers to – and which I’ve never seen referred to before – that the placebo response may, to some extent, be determined by adherence.
“However, we still need to know a lot more about why people stayed on methotrexate and what the differences were at baseline,” he added, “because that’s not corrected for in a post hoc analysis.”
The finding clearly paved the way for further research, Professor Hall said.
“I would conclude [from this study] that the decision making and mindset that underlies adherence to one treatment recommendation needs to be dissected out to a greater extent so we can harness its power to ensuring adherence across the board,” he said.
